In animals and humans, stress and corticosteroid excess are associated with changes in hippocampal structure and functioning. These findings have important implications for 1) patients with mood disorders, because subsets of people with major depressive disorder and bipolar disorder have elevated cortisol and memory impairment, and 2) the estimated 1% of the population treated with prescription corticosteroids for medical illnesses. Icariin, a flavonoid from Epimedium, 1) blocks the effects of corticosteroid-induced apoptosis in primary cultured rat hippocampal neurons, 2) is neuroprotective in animal models of ischemia, 3) improves memory in animal models of cognition, and 4) has antidepressant properties in an animal model of depression. Despite these promising pre-clinical findings, and the widespread availability of icariin in over-the-counter supplements, no studies have examined the effects of this compound on the human brain or examined its pharmacokinetics in humans. Only one human controlled trial of icariin has been reported, to date. In this report icariin appeared to be safe, well tolerated and effective when given to women for bone loss. Our group has a research program using patients in medical settings receiving prescription corticosteroid (e.g. prednisone) therapy or healthy controls receiving brief corticosteroid exposures in a laboratory paradigm as models to explore the effects of cortisol elevations on the human brain. A major current focus of our work is on medications that may block the effects of stress or corticosteroids on the hippocampus (a brain region essential for memory). We have identified several promising agents. We propose to explore whether icariin will block the effects of hydrocortisone (cortisol) on memory in healthy controls. The current proposal has two phases. In Phase I the pharmacokinetics of icariin, and the safety and tolerability of two icariin doses wil be assessed. This will provide needed data for the second phase of this proposal, and for other future human research with icariin. In Phase II we will determine whether icariin blocks the effects of corticosteroids on memory using our paradigm. This experiment will examine icariin both alone and in combination with hydrocortisone in healthy controls using a battery of cognitive tests and mood assessments. Safety and tolerability will also be monitored. A highly experienced research team that has completed and published studies with similar designs as in the current proposal will conduct the project.